Mole rats evolved to cope with oxygen-poor tunnels

Blind mole rats live in underground burrows that can be quite hypoxic, with oxygen levels getting as low as 7.2 percent. (The air we breathe is 21 percent oxygen). A team of researchers in Israel and Germany have determined that Spalax have evolved to tolerate this environment by expressing more of their oxygen-carrying globins than other rats, which help them survive at low ambient oxygen levels.

The globin family is comprised of proteins responsible for the delivery and storage of oxygen throughout the body. Hemoglobin (Hb), in red blood cells, transports oxygen from the lungs through the blood to the inner organs. Myoglobin (Mb) is expressed in striated and cardiac muscles; it acts as localized oxygen storage, and helps disperse the oxygen as needed throughout the relatively large muscle cells.

Ten years ago, two unique mammalian globins were discovered. Neuroglobin (Ngb) is found in neurons of both the central and peripheral nervous systems, and in endocrine organs. Ngb is also expressed in astrocytes in mammals tolerant of hypoxia—like these mole rats and the deep diving hooded seal—but not in those sensitive to hypoxia, like mice and rats. Ngb is highly colocalized with mitochondria, and thus active oxidative metabolism, but its function is not yet clear; it may act in the brain like Mb acts in muscle, to supply oxygen to the mitochondrial respiratory chain, or it may scavenge reactive oxygen species. Cytoglobin (Cygb) is found in fibroblasts, and its role is even more obscure than Ngb’s.

Spalax are known to have increased levels of Hb, and their Hb has a high affinity for oxygen. In recent work, the researchers compared the sequences and expression levels of the other globin genes among the different Spalax species with those of the hypoxia sensitive rat, under both normoxic and hypoxic conditions.

They had access to 4 different allospecies of the blind mole rat Spalax from Israel. These animals cope with hypoxia to varying degrees depending on the different climates in the regions where they live. Spalax galili live in the Galilee, the Northern part of the country, which is cool and moist; they have the most efficient hypoxic adaptation. Spalax judaei live in the Judean desert to the south, which is warm and dry.

These proteins are highly conserved among the Spalax species, so a difference in function did not seem to account for their different abilities to tolerate hypoxia. Spalax expressed 2-3 fold more Ngb RNA and protein than rats under normal conditions. Upon short term severe hypoxic stress, however—five hours at six percent oxygen—normal rats and S. judaei downregulated their Ngb mRNA by almost twofold but S. galili did not. Twenty-two hours of ten percent oxygen were required to bring their Ngb mRNA levels down. Even after hypoxia reduced Ngb mRNA, Ngb protein levels stayed constant in the mole rats, but not the other rats.

Spalax expressed two- to three-fold more Cygb mRNA and protein than normal rats under normoxia as well, but only in the brain, not in the heart or liver (muscle tissues). When the animals were placed under hypoxic conditions, Cygb mRNA stayed constant in rat brains but increased two fold in mole rat brains. And it increased two fold in rat hearts, but twelve fold in mole rat hearts.

The mole rats also expressed more Mb than normal rats. In neck muscle, which the mole rats use for digging, S. judaei had 27 fold and S. galili had 44 fold Mb mRNA than other rats. Short term severe hypoxia did nothing to Spalax Mb mRNA levels, but rat Mb mRNA levels increased threefold.

When humans are deprived of oxygen, we lose consciousness within minutes. Subterranean mole rats, in contrast, just continue digging their tunnels. Their higher levels of Hb, Mb, Ngb and Cygb protein help them to survive with chronic hypoxia. Perhaps we can exploit this system to help human cells survive hypoxic stresses, such as those precipitated by a heart attack or stroke.